Research

JAMA Neurology | Original Investigation Fenfluramine for Treatment-Resistant Seizures in Patients With Receiving Stiripentol-Inclusive Regimens A Randomized

Rima Nabbout, MD, PhD; Arun Mistry, MBChB, MRCP(UK), MRCPCH; Sameer Zuberi, MD; Nathalie Villeneuve, MD; Antonio Gil-Nagel, MD; Rocio Sanchez-Carpintero, MD; Ulrich Stephani, MD; Linda Laux, MD; Elaine Wirrell, MD; Kelly Knupp, MD; Catherine Chiron, MD, PhD; Gail Farfel, PhD; Bradley S. Galer, MD; Glenn Morrison, PhD; Michael Lock, PhD; Anupam Agarwal, MD; Stéphane Auvin, MD, PhD; for the FAiRE, DS Study Group

Supplemental content IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens.

OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens.

DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens.

INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary.

MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline.

RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (Ն50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.

CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. Author Affiliations: Author TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02926898 affiliations are listed at the end of this article. Group Information: The FAiRE, DS Study Group members appear at the end of the article. Corresponding Author: Bradley S. Galer, MD, Zogenix, 5959 Horton St, JAMA Neurol. doi:10.1001/jamaneurol.2019.4113 Ste 500, Emeryville, CA 94608 Published online December 2, 2019. ([email protected]).

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ravet syndrome (DS) is a severe developmental epi- leptic encephalopathy with an incidence of 1:15 700 to Key Points 1:40 900.1 Dravet syndrome typically presents in the D Question Is fenfluramine safe and effective for treating patients first year of life with frequent, pharmacoresistant convulsive with Dravet syndrome who have frequent seizures despite taking seizures,1,2 which may contribute to intellectual disability and a stiripentol-inclusive antiepileptic drug regimen? impairments in motor control, behavior, and cognition.3 Most Findings Oral fenfluramine (0.4 mg/kg/d; maximum 17 mg/d) patients (70%-85%) have sodium voltage-gated channel al- provided a 54.0% greater reduction in mean monthly convulsive pha subunit 1 gene (SCN1A) sodium channel alterations, al- seizure frequency than placebo in patients with Dravet syndrome though diagnosis is solely based on electroclinical criteria.1,2,4 who were taking stiripentol-containing antiepileptic drug Patients with DS who are younger than 18 years have in- regimens; a significantly greater proportion of patients who were creased risk of sudden unexpected death in epilepsy, with a taking fenfluramine (vs placebo) experienced a clinically Ն Ն mortality rate of 7% to 18%. Frequency of generalized tonic- meaningful ( 50%) or profound ( 75%) reduction in monthly convulsive seizure frequency. The most common adverse events clonic seizures is a major risk factor for this outcome.5-7 included decreased appetite, pyrexia, fatigue, and diarrhea; no Even with polypharmacy, seizures remain poorly con- patient developed valvular heart disease or pulmonary trolled in most patients with DS. In a survey of 274 patients, hypertension. 45% receiving multitreatment modalities continued to expe- Meaning Adjunctive fenfluramine may be a safe, effective new rience more than 4 tonic-clonic seizures per month.8 Until the treatment option for patients with Dravet syndrome with seizures recent approval of and stiripentol by the US Food that are not controlled by a regimen including stiripentol. and Drug Administration, stiripentol in combination with val- proate and remained the only approved treatment for DS outside of the United States. Despite treatment with stiripentol-inclusive antiepileptic drug (AED) regimens, 38% The study complied with current International Council for of patients were reported to present with weekly seizures Harmonisation Good Clinical Practice guidelines, as de- (>3 per month).8,9 Given the risks of sudden unexpected death scribed in International Council for Harmonisation Topic E6 in epilepsy, cognitive deficits, and other neurological conse- Guidelines.14 The protocol was approved by applicable regu- quences putatively caused at least in part by poorly con- latory authorities and an independent ethics committee or in- trolled seizures, there remains an urgent unmet need for treat- stitutional review board at each participating institution. All ing DS.9-11 patients or their legal representatives provided written in- Results from a recent phase 3, placebo-controlled random- formed consent before enrollment. ized clinical study (Study 1 [NCT02682927; NCT02826863])12 demonstrated that fenfluramine provided a significantly Patients and Eligibility Criteria greater reduction in monthly convulsive seizure frequency Patients were male or female; aged 2 to 18 years (inclusive); (MCSF) vs placebo. Patients receiving stiripentol were ex- receiving a stable, stiripentol-inclusive AED regimen; and free cluded from Study 1 because pharmacokinetic data were not of cardiovascular disease on an echocardiogram, electrocar- yet available to evaluate dosage modifications needed to com- diogram, or physical examination. The diagnosis of DS was vali- pensate for an expected fenfluramine-stiripentol drug inter- dated by a central committee, the Epilepsy Study Consor- action. Given the widespread use of stiripentol for DS, it is im- tium (eTable 1 in Supplement 1). Key exclusion criteria were portant to assess the benefit and tolerability of add-on pulmonary arterial hypertension (PAH) or a current condi- fenfluramine in stiripentol-containing AED regimens. A phase tion or history of cardiovascular or cerebrovascular disease 1 pharmacokinetic study and earlier physiologically based phar- (eg, cardiac valvulopathy, myocardial infarction, stroke) and macokinetic modeling were used to select a fenfluramine dose concomitant treatment with modulators of serotonergic ac- of 0.4 mg/kg/d (maximum, 17 mg/d) added to stiripentol- tivity, AEDs with sodium channel antagonist activity, or can- -clobazam triple therapy.13 Here, we evaluate effi- nabinoid products. cacy and safety of add-on fenfluramine in patients with DS re- ceiving stiripentol-inclusive AED regimens. Trial Procedures This study evaluated the safety and efficacy of twice-daily fen- fluramine (administered as a fenfluramine hydrochloride oral Methods solution containing 2.2 mg/mL of fenfluramine) added to a stiripentol-inclusive AED regimen (plus valproate or cloba- Trial Design, Ethics, and Oversight zam, at a minimum) in children and young adults with DS In this double-blind, parallel-group, placebo-controlled, phase (eFigure 1 in Supplement 1). In a drug-interaction study (Co- 3 randomized clinical study, patients with DS with seizures that hort 1 [NCT02926898]), fenfluramine was administered with were poorly controlled with current AED regimens, which had clobazam and valproate and with and without stiripentol. Data to include stiripentol plus clobazam or valproic acid, were en- from this study and a phase 1 study in healthy adults15 were rolled at approximately 28 sites in Canada, France, Germany, used in an early version of a physiologically based pharmaco- the Netherlands, Spain, the United Kingdom, and the United kinetic model to help select fenfluramine dose for this study States (NCT02926898; eFigure 1 in Supplement 1; trial protocol (Study 1504, Cohort 2 [NCT02926898]; 0.4 mg/kg/d; maxi- in Supplement 2). mum dosage, 17 mg/d).

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After a 6-week period to establish baseline seizure fre- Statistical Analyses quency, patients were randomized (1:1, via interactive web re- Sample size was based on results from previous placebo- sponse system) to fenfluramine or matching placebo groups controlled randomized clinical studies in patients with in a double-blind manner, using sequentially numbered bottles DS.8,9,18-22 An SD of 55% was assumed for the primary analy- for treatments. Randomization was stratified across ages sis. Using a 2-sided test with α = .05 as a threshold, a sample (<6 years vs ≥6 years) to ensure balance across treatments. The size of at least 80 total patients (40 patients per treatment fenfluramine starting dosage was 0.2 mg/kg/d in 2 equal doses, group) affords 90% power to detect a 40–percentage point dif- with a gradual blinded titration to 0.4 mg/kg/d (maximum, ference in mean change from baseline. The Statistical Analy- 17 mg/d) over 3 weeks (eTable 2 in Supplement 1). Patients sis Plan is in Supplement 3. maintained their use of fenfluramine or placebo for an addi- tional 12 weeks at a stable dosage, then either continued treat- Analysis Population ment in an open-label extension study or discontinued treat- Safety analyses were performed on all randomized patients ment with a blinded, downward dose–tapering protocol who received 1 or more doses of fenfluramine or placebo. The (eTable 2 in Supplement 1). Caregivers recorded doses, any res- primary end point analysis and the key secondary analyses per- cue medication, and the number and type of seizures in hand- formed on the modified intent-to-treat population included held electronic diaries. all randomized patients who received 1 or more doses of fen- fluramine or placebo with 1 week or more of seizure diary data. Safety Treatment-emergent adverse events among the placebo Statistical Methods and fenfluramine subgroups were recorded throughout Continuous variables were summarized using descriptive sta- study duration. Standardized color Doppler echocardiogra- tistics (means with SDs, medians with interquartile or full phy assessed cardiac valve function and structure and ranges, and 95% CIs). Categorical variables were summarized any evidence of PAH at study baseline (prior to participants’ with frequencies and percentages. The distribution of base- receiving any study drugs; days −42 to −21), during the line characteristics across treatment groups was assessed using maintenance period (days 40 to 54), at the end of study Wilcoxon rank sum for continuous variables (age, body mass (between days 90 and 113), and during cardiac follow-up index [calculated as weight in kilograms divided by height in visits (3 and 6 months posttreatment; care was extended up meters squared], and baseline MCSF), Fisher exact test for di- to 24 months in some countries). Primary assessment was chotomous variables (age group and sex), and Freeman- done to detect the presence of valvular regurgitation on Halton test for categorical variables (race/ethnicity and num- the aortic and mitral valve, although all valves were ber of concomitant AEDs). The primary efficacy end point was assessed. Assessments were graded as absent, trace, mild, analyzed using an analysis of covariance model with treat- moderate, or severe. Blinded core laboratory readers from ment group and age group (<6 years and ≥6 years) as factors eResearchTechnology Inc (ERT) Clinical evaluated all and baseline frequency as a covariate. The primary analysis echocardiograms for presence and grade of cardiac valve compared the fenfluramine group with the placebo group with regurgitation and PAH. Electrocardiograms were also a 2-sided test (with an α = .05 significance threshold). Effi- evaluated by core laboratory readers (ERT Clinical) for any cacy analyses used a serial gatekeeper approach with a hier- abnormality. archy of significance tests to maintain a type I error rate with α = .05 across analyses. The testing order was (1) change in Efficacy End Points MCSF from baseline, (2) the proportion of patients achieving The primary efficacy end point was a comparison of the dif- 50% MCSF reduction or greater from baseline, and (3) the lon- ference between fenfluramine and placebo on the change in gest convulsive seizure–free interval. mean MCSF from baseline to the combined titration and The proportion of patients achieving 50% reduction in MCSF maintenance (T + M) periods. The key secondary efficacy or greater during the T + M period was analyzed using a logistic end points were the proportion achieving 50% or greater regression model that incorporates the same factors and covar- reduction from baseline levels in MCSF and the duration iate as the analysis of covariance in the primary analysis. For the of the longest seizure-free interval. Other secondary end longest interval between convulsive seizures during the T + M points included the proportion of patients with 0 seizures period, treatment groups were compared using a Wilcoxon rank or 1 seizure during the T + M periods, the proportion with sum test. For assessing clinical global impression improvement, 25% or more, 75% or more, and 100% reduction in seizures patients rated as showing any improvement (scores ≤3) or clini- from baseline, change from baseline in clinical global cally meaningful improvement (≤2) vs no improvement (scores impression ratings by both parents or caregivers and investi- ≥4 or ≥3, respectively) were compared using the Cochran-Mantel- gators, days of rescue medication use per 28 days, and Haenszel test (fenfluramine vs placebo). total seizure frequency (including nonconvulsive seizure Frequency of treatment-emergent adverse events and se- types) per 28 days. Patient quality of life and executive func- rious adverse events were presented by treatment group using tion were assessed by the Quality of Life in Childhood the Preferred Term from the Medical Dictionary for Regula- Epilepsy Scale,16 Pediatric Quality of Life Inventory,17 tory Activities (MedDRA). Results of electrocardiogram and and Behavior Rating Inventory of Executive Function Doppler echocardiogram analyses were summarized by treat- instruments. ment group using descriptive statistics.

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Efficacy Figure 1. Patient Disposition The study achieved its primary efficacy objective: patients ran- domized to fenfluramine achieved an estimated 54.0% 115 Screened for eligibility (95% CI, 35.6%-67.2%) greater reduction in mean MCSF be- tween the baseline and T + M periods than those who re- 28 Excluded at screening ceived placebo (P < .001; Table 2). Significantly more pa- tients in the fenfluramine group than the placebo group experienced a clinically meaningful (≥50%) reduction in mean 87 Randomized to treatment MCSF (fenfluramine group, 23 of 43 [54%] vs placebo group, 2of44[5%];P < .001) and significantly longer seizure-free in- 44 To placebo arm 43 To fenfluramine arm tervals (median [range], 22.0 [3.0-105.0] days vs 13.0 [1.0- (0.4 mg/kg/d) 40.0] days; P = .004). The median percentage reduction from baseline in MCSF 7 Withdrew in the fenfluramine group was 63.1% (range, −100.0% to 2 Adverse event 3 Withdrew 115.0%), compared with 1.1% (range, −82.8% to 435.1%) in the 1 Protocol deviation 1 Adverse event 1 Lack of efficacy placebo group during the T + M periods (P < .001; Table 2). The 1 Early transition to OLE 1 Worsening of seizures 1 Uncontrolled seizures median number of convulsive seizure–free days was signifi- 1 Physician decision 1 Patient decision cantly higher in patients treated with fenfluramine than pla- cebo (median [range]: fenfluramine group, 24.4 [1.9-28.0] days vs placebo group, 20.3 [0.0-26.4] days; P = .001). 77 Completed the study A significantly greater proportion of patients achieved a 25% or greater, 50% or greater, or 75% or greater reduction in MCSF in the fenfluramine group than placebo (fenfluramine 41 In placebo arm 36 In fenfluramine arm group: 30 of 43 [70%], 23 of 43 [54%], and 15 of 43 [35%] vs placebo group, 12 of 44 [27%], 2 of 44 [5%], and 1 of 44 [2%],

OLE indicates open-label extension. respectively; Figure 2). There was no difference in the num- ber of patients experiencing complete seizure freedom (1 of 43 [2%] in the fenfluramine group vs 0 in the placebo group); how- ever, 5 of 43 patients treated with fenfluramine (12%) experi- Results enced no more than a single convulsive seizure during the T + M periods (compared with 0 patients treated with pla- Patient Disposition cebo; P = .03). The significant reduction in MCSF vs placebo A total of 115 patients were screened for eligibility, with 87 pa- was apparent at the first assessment (maintenance week 2; tients randomized to treatment (44 to placebo and 43 to fen- T + M week 5) and was consistently maintained throughout the fluramine); 77 completed the study (41 who received placebo 15-week combined T + M periods (eFigure 2 in Supple- and 36 who received fenfluramine; Figure 1). Most patients who ment 1). Patients treated with fenfluramine achieved a me- failed screening did not meet the randomization criteria (26 dian 41.1% (range, −100.0% to 133.2%) decrease from base- of 28 patients [93%]), including meeting baseline seizure fre- line in total seizure frequency vs 5.9% (range, −73.8% to quency, echocardiogram requirements, and compliance with 375.6%) for those receiving placebo (P = .003) (Table 2). daily seizure diary; additionally, 1 patient elected to with- Days of rescue medication use were low in both treat- draw during screening, and 1 withdrew because of use of a pro- ment groups at baseline. Patients in the fenfluramine treat- hibited medication. Of those randomized, 3 in the placebo ment group experienced a numerically greater (although sta- group and 7 in the fenfluramine group withdrew early tistically insignificant) reduction in days of rescue medication (Figure 1). use (Table 2). At the end of the T + M period, 19 of 43 investigators (44%) Patient Baseline Characteristics and 14 of 43 caregivers (33%) rated patients in the fenfluramine Most patients were male (placebo group, 27 of 44 [61%]; fen- treatment group as much improved or very much improved vs fluramine group, 23 of 43 [54%]; Table 1) and between 6 and 7 of 44 (16%) and 9 of 44 (21%), respectively,in the placebo group 19 years old (placebo group, 32 of 44 [73%]; fenfluramine group, (P = .008 and P = .14) (eFigure 3 in Supplement 1). Significantly 31 of 43 [72%]). Baseline MCSF was comparable in both groups more patients receiving fenfluramine than placebo were rated (mean [SD]: placebo group, 21.6 [27.7] seizures; fenfluramine as having any improvement (including being minimally im- group, 27.9 [36.9] seizures). Most patients were receiving either proved) by both investigators (fenfluramine group, 31 of 43 3 concomitant AEDs (placebo group, 26 of 44 [59%]; fenflur- [72.1%] vs placebo group, 14 of 44 [31.8%]; P < .001) and care- amine group, 19 of 43 [44%]) or 4 concomitant AEDs (placebo givers (fenfluramine group, 26 of 43 [60.5%] vs placebo group, group, 16 of 44 [36%]; fenfluramine group, 16 of 43 [37%]). Be- 16 of 44 [36.4%]; P = .009). There were no significant differences sides the protocol-specified stiripentol, the most frequent AEDs noted between groups on the Quality of Life in Childhood Epi- were clobazam, , , and valproate (all lepsy Scale, Pediatric Quality of Life Inventory,and Behavior Rat- forms) (Table 1). ing Inventory of Executive Function.

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Table 1. Patient Baseline Characteristics

Patients, No. (%) Receiving P Characteristic Fenfluramine Receiving Placebo Total Valuea No. 43 44 87 NA Age, mean (SD) [range], y 8.8 (4.6) [2-18] 9.4 (5.1) [2-19] 9.1 (4.8) [2-19] .57 Patients <6 y 12 (28) 12 (27) 24 (28) >.99 Abbreviations: AED, antiepileptic Male 23 (53) 27 (61) 50 (57) .52 drug; BMI, body mass index Race (calculated as weight in kilograms White 23 (53) 29 (66) 52 (60) divided by height in meters squared); NA, not applicable; NC, not Black/African American 1 (2) 2 (5) 3 (3) calculated. Asian 2 (5) 1 (2) 3 (3) a .66 P values (fenfluramine vs placebo) Other 3 (7) 1 (2) 4 (5) were calculated by Wilcoxon rank Not reported or missingb 13 (30) 11 (25) 24 (28) sum test (age, BMI, and baseline convulsive seizure frequency per 28 Unknown 1 (2) 0 (0) 1 (1) days), Fisher exact test (age group BMI, mean (SD) 17.3 (2.7) 19.1 (4.9) 18.2 (4.0) .11 and sex), and Freeman-Halton test Convulsive seizure frequency per 28 d (race and number of concomitant AEDs) with statistical significance Median (range) 14.0 (3-213) 10.7 (3-163) NA .62 set at P less than .05. Mean (SD) 27.9 (36.9) 21.6 (27.6) NA b Not reported or missing: privacy No. of concomitant AEDs at baseline laws in some regions and countries 2 1 (2) 1 (2) 2 (2) preclude disclosure of certain personal information. 3 19 (44) 26 (59) 45 (52) .10 c Concomitant medications in less 4 16 (37) 16 (36) 32 (37) than 10% of patients included 5 7 (16) 1 (2) 8 (9) , , Other antiepileptic treatments in ≥10% , , of subgroupc,d , gamma-aminobutyric Stiripentol 43 (100) 44 (100) 87 (100) acid, , , , and . Clobazam 40 (93) 42 (96) 82 (94) d The number of patients following a Valproate 38 (88) 39 (89) 77 (89) NC ketogenic diet was 4 (5%) in the Topiramate 14 (33) 7 (16) 21 (24) overall population. The number of patients with vagal nerve stimulator Levetiracetam 6 (14) 5 (11) 11 (13) implantation was 5 (6%) overall.

Safety cebo), 6 patients had trace mitral regurgitation findings at week The most common treatment-emergent adverse events in the 8 that were not present at week 14; 5 patients had trace mitral fenfluramine group included decreased appetite, pyrexia, fa- regurgitation findings at week 14 only; and 1 patient had trace tigue, and diarrhea (Table 3). Treatment-emergent adverse mitral regurgitation at both weeks 8 and 14. events–associated discontinuations occurred in 3 patients. Two patients (4.5%) receiving placebo and 9 patients (20.9%) re- ceiving fenfluramine experienced weight decreases of 7% or Discussion more from baseline. Of these patients, 5 were also receiving topiramate (another AED with anorectic properties). This study achieved its primary objective, demonstrating No cases of valvular heart disease (VHD) or PAH were ob- that adding fenfluramine to stiripentol-containing AED regi- served in any patient at any time during the study. Echocar- mens provided significant reduction in MCSF in patients diographic monitoring demonstrated that all patients were with DS. A significant reduction in MCSF was achieved at the within the normal physiologic range at all points for mitral and earliest point measured (week 2 of the maintenance period) aortic valve function, as well as pulmonic and tricuspid valve and was maintained throughout the 15-week T + M period. function. No abnormalities in valve structure were reported. In addition, a significantly greater proportion of patients Observed valve regurgitation in the T + M periods was lim- achieved a 50% or greater or 75% or greater reduction in ited to trace mitral regurgitation and 1 echocardiogram find- MCSF in the fenfluramine vs placebo groups. Also, a signifi- ing of mild mitral regurgitation in a patient who also had a cantly greater proportion of patients treated with fenflur- screening echocardiogram finding of mild mitral regurgita- amine experienced no more than 1 convulsive seizure during tion at baseline. Trace mitral regurgitation is not a pathologic the entire T + M period vs placebo. Investigators reported finding; rather, it is a normal physiologic finding on echocar- that significantly more patients in the fenfluramine group diogram commonly seen in normal, healthy children.23 Ob- had clinically meaningful improvements in clinical global servations of trace mitral regurgitation were largely sporadic. impression scores (ie, they were rated much improved Of the 12 patients who had trace mitral regurgitation at any or very much improved). Both caregivers and parents and point (including 9 receiving fenfluramine and 3 receiving pla- investigators reported statistically significant differences

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Table 2. Efficacy End Points in the Combined Titration and Maintenance Period

Patients Receiving Patients Receiving End Point Fenfluramine (n = 43) Placebo (n = 44) P Value Primary and Key Secondary End Points Estimated difference from placebo in convulsive 54.0 (35.6-67.2) 1 [Reference] <.001 seizure frequency per 28 d, % (95% CI)a Reduction in MCSF from baselineb ≥50%, No. (%) 23 (54) 2 (5) <.001 Odds ratio (95% CI) 26.0 (5.5-123.2) 1 [Reference] Longest convulsive seizure-free interval, db Mean (SD) 29.7 (27.3) 13.4 (7.5) .004 Median (range) 22.0 (3.0-105.0) 13.0 (1.0-40.0) Other Secondary End Points Reduction in mean MCSF from baselinec ≥25% No. (%) 30 (70) 12 (27) <.001 Odds ratio (95% CI) 6.4 (2.5-16.5) 1 [Reference] ≥75% No. (%) 15 (35) 1 (2) .003 Odds ratio (95% CI) 23.7 (2.9-191.8) 1 [Reference]

Seizure freedom or near seizure freedom, No. (%) Abbreviations: MCSF, monthly [95% CI] convulsive seizure frequency; 0 Convulsive seizures 1 (2) [0.1-12.3] 0 (0) [0.0-8.0] .49 NA, not applicable. ≤1 Convulsive seizure 5 (12) [3.9-25.1] 0 (0) [0.0-8.0] .03 a Primary outcome. Percentage change from baseline in convulsive −63.1 (−100.0 to 115.0) −1.1 (−82.8 to 435.1) <.001 b Key secondary outcome. seizure frequency per 28 d, median (range) c Odds ratios are calculated for Nonconvulsive seizure frequency per 28 dd comparisons with outcomes in the No. of patients (%) 17 (40) 22 (50) NA placebo group. An age-adjusted Percentage change from baseline per 28 d, −0.5 (−100.0 to 611.2) −49.7 (−100.0 to 529.4) .18 logistic regression model was used median (range) to estimate all odds ratios, except Percentage change from baseline in total seizure −41.1 (−100.0 to 133.2) −5.9 (−73.8 to 375.6) .003 for those comparing fenfluramine frequency per 28 d, median (range) with placebo at the 25% and 75% No. of days of rescue medication use per 28 d seizure-reduction response levels, for which the age adjustment was Baseline, mean (SD) 2.1 (2.6) 1.4 (2.5) NA eliminated because of potential Combined titration and maintenance periods, 1.4 (2.2) 1.2 (2.6) .25 model instability. Note that an odds mean (SD) ratio larger than 1.00 can be much Nonseizure Outcomes, No. (%) larger than the corresponding Clinical global impression of improvemente relative risk. d Very much improved or much improved Not all patients had nonconvulsive seizures. Parent/caregiver rating 14 (33) 9 (21) .14 e P values from the Investigator rating 19 (44) 7 (16) .008 Cochran-Mantel-Haenszel test Any improvementf controlling for age group. Parent/caregiver rating 26 (61) 16 (36) .009 f Includes the responses “very much improved,” “much improved,” and Investigator rating 31 (72) 14 (32) <.001 “minimally improved.”

between treatment groups in any improvement (ie, those Similarly, patients entering the current study were expe- rated minimally improved or better). riencing high numbers of seizures at baseline, as high as 1 Stiripentol, used since the early 2000s, has been ap- seizure per day (or more in some patients). Thus, patients proved in Europe, Japan, and Canada, and as per labeled in- enrolled in this study experienced significant and clinically structions, it must be coprescribed with clobazam and valpro- meaningful improvements with fenfluramine added to ate. Stiripentol was approved by the US FDA in 2018, and per their current stiripentol-containing AED regimen (54.0% US label, it must be coprescribed with clobazam. Prior con- [95% CI, 35.6%-67.2%] greater reduction in mean MCSF trolled trials have reported stiripentol efficacy in reducing sei- vs patients treated with placebo). The magnitude of treat- zure frequency when used in combination with clobazam and ment outcome is further highlighted by the fact that signifi- valproate-containing regimens; however, most patients con- cantly more patients with added fenfluramine vs placebo tinue to experience seizures.8,9,18-20 In 1 study,9 despite treat- experienced reductions in MCSF that were clinically mean- ment with stiripentol and 3 to 4 other AEDs, 79% of patients ingful (≥50%; 54% vs 5%) and profound (≥75%; 35% vs with DS continued to experience weekly or monthly seizures 2%), which are magnitudes of response not commonly seen at follow-up a median of 8 years in length. in DS.

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Figure 2. Cumulative Response Curves for Percent Reduction Table 3. Most Common (≥10%) Noncardiovascular Treatment-Emergent in Monthly Convulsive Seizure Frequency From Baseline Adverse Events in Any Treatment Group

100 Patients, No. (%) Receiving Receiving Fenfluramine Placebo 80 Outcome (n = 43) (n = 44) Patients with ≥1 treatment-emergent 42 (98) 42 (96) adverse event. 60 Patients with ≥1 serious 6 (14) 7 (16) treatment-emergent adverse event. Treatment-emergent adverse events in

Patients, % 40 ≥10% of patients in any treatment group Fenfluramine Decreased appetite 19 (44) 5 (11) 20 Pyrexia 11 (26) 4 (9)

Placebo Fatigue 11 (26) 2 (5) 0 Diarrhea 10 (23) 3 (7) 0 10 20 30 40 50 60 70 80 90 100 Nasopharyngitis 7 (16) 15 (34) Reduction in Mean Convulsive Seizure Frequency, % Blood glucose decreased 6 (14) 2 (5) Results are plotted for combined titration and maintenance periods. Vertical Lethargy 6 (14) 2 (5) dashed lines represent 25%, 50%, and 75% reduction in monthly convulsive Bronchitis 5 (12) 2 (5) seizure frequencies; percentages correspond to the proportion of patients in the fenfluramine or placebo groups who met or exceeded each response level. Seizure 2 (5) 7 (16) Twelve of 44 patients (27%) in the placebo group and 30 of 43 (70%) in the fenfluramine group experienced 25% or greater reductions (P <.001);2of44 patients (5%) in the placebo group and 23 of 43 (54%) in the fenfluramine tive to the higher dosages for adults with obesity.12,31,32 Weight group experienced 50% or greater reductions (P <.001);and1of44(2%)inthe loss occurred but at rates commensurate with previous clini- placebo group and 15 of 43 (35%) in the fenfluramine group experienced 75% 22 reductions (P = .003). The P values are vs placebo and are estimated by logistic cal studies, and none of the patients experienced weight loss regression (as per Table 2). that resulted in trial discontinuation.

Fenfluramine was generally well tolerated. Importantly, Study Limitations no patient developed valvular heart disease or PAH, and all Outcomes associated with fenfluramine (eg, appetite suppres- echocardiograms in all patients demonstrated normal valve sion, efficacy in MCSF reduction) could theoretically lead to function without observation of abnormal valve morphol- functional unblinding, but post hoc analyses found no evi- ogy. Fenfluramine as an anorectic agent for adults was re- dence of this. The study duration was short, and longer-term moved from the market in 1997 based on reports of increased observations will be necessary to fully characterize long- risk of valvular heart disease when prescribed in higher dos- term effectiveness and safety, including developmental end ages (60-120 mg/d) and (most often) when prescribed with points and an cardiovascular safety profile. However, 1 open- phentermine.24 In addition, cases of PAH were also reported.25 label study30 (treatment up to 30 years in Belgium) and an In the patient population of adults with obesity, higher dos- open-label extension to the phase 3 studies33,34 (treatment up ages (>40-60 mg daily) than those required for efficacy in the to 3 years) have reported continued, significant improve- current study (≤17 mg/d) were reported.26-30 Importantly, an ment in MCSF reduction without development of valvular heart intensive, prospectively defined cardiovascular monitoring disease or PAH. program was used, with color Doppler echocardiographic ex- aminations before and during the trial to identify functional changes in cardiac valves and signs of PAH, and all echocar- Conclusions diograms were interpreted by 2 reviewers blinded to treat- ment group. There was no valvular heart disease or PAH ob- Fenfluramine demonstrated statistically significant and clini- served in any patient at any time during the study. Only findings cally meaningful efficacy in this phase 3 trial in patients with of intermittent, trace mitral regurgitation were observed, which DS currently receiving a stiripentol-containing AED regimen are physiologic findings also observed in children with nor- without the development of valvular heart disease or PAH. Fen- mal health.23 This study supports previous reports of the car- fluramine may represent an important, effective new treat- diovascular safety in patients with DS at the lower dosages used ment option for patients with DS and seizures inadequately for seizure management in short-term and long-term trials rela- controlled on stiripentol-inclusive AED regimens.

ARTICLE INFORMATION Open Access: This is an open access article Recherche Médicale, Unite Mixté de Recherche Accepted for Publication: October 12, 2019. distributed under the terms of the CC-BY-NC-ND 1163, Paris Descartes University, Paris, France License. © 2019 Nabbout R et al. JAMA Neurology. (Nabbout); Zogenix, Inc, Emeryville, California Published Online: December 2, 2019. (Mistry, Farfel, Galer, Morrison, Lock, Agarwal); doi:10.1001/jamaneurol.2019.4113 Author Affiliations: Hôpital Universitaire Necker– Enfants Malades, Service de Neurologie Pédiatrique Paediatric Neurosciences Research Group, Royal Centre de Référence Épilepsies Rares, Imagine Hospital for Children Glasgow, Glasgow, United Institute, Institut National de la Santé et de la Kingdom (Zuberi); Assistance Publique–Hôpitaux

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de Marseille, Department of Pediatric Neurology, Dr Auvin also reports personal fees from Arvelle Universitaetsklinik fuer Kinder-und Jugendmedizin Hôpital de la Timone, Marseille, France (Villeneuve); and Biocodex; personal fees and nonfinancial Abteilung III, Tübingen, Germany; Domenica Hospital Ruber Internacional, Madrid, Spain support from Biomarin, GWPharma, and Nutricia; Battaglia, MD, Policlinico A. Gemelli Day Hospital di (Gil-Nagel); Pediatric Neurology Unit, Clínica personal fees and grants from Eisai, UCB Pharma, Neuropsichiatria Infantile, Rome, Italy; Francesca Universidad de Navarra, Pamplona, Spain and Advicenne Pharma for work as an investigator; Beccaria, MD, A.O. Carlo Poma Unità Operativa di (Sanchez-Carpintero); Department of and nonfinancial support from Vitaflo. Dr Gil-Nagel Neuropsichiatria dell'Infanzia e dell'Adolescenza Neuropediatrics, Christian-Albrechts-University, also reports personal fees from Bilal, GWPharma, Centro Regionale per I'Epilessia, Mantova, Italy; Kiel, Germany (Stephani); Ann & Robert H. Lurie Zogenix, Stoke Therapeutics, Eisai, and Esteve. No Francesca Darra, MD, Ospedal Policlinico Children’s Hospital of Chicago, Northwestern other disclosures were reported. Giambattista Rossi diBorga Roma, Verona, Italy; University Feinberg School of Medicine, Chicago, Funding/Support: This study was funded by Tiziana Granata, MD, Istituto Neurologica Carlo Illinois (Laux); Mayo Clinic, Rochester, Minnesota Zogenix. Besta, Rome, Italy; Renzo Guerrini, MD, AOU Anna (Wirrell); University of Colorado, Children’s Hospital Meyer Clinica di Neurologia Pediatrica, Florence, Colorado, Aurora (Knupp); Pediatric Neurology, Role of the Funder/Sponsor: Zogenix, in Italy; Antonio Romeo, MD, Ospedale Necker-Enfants Malades Hospital, Institut National collaboration with study investigators and the Fatebenefratelli e Oftalmico, Milan, Italy; Pasquale de la Santé et de la Recherche Médicale Unite 1141, contracted clinical research organizations (Premier Striano, MD, Istituto Pediatrico Giannina Gaslini Paris, France (Chiron); Robert Debré University Research and Syneos Health), were responsible for Dipartimento di Neurologia, Genova, Italy; Federico Hospital, Université de Paris, Institut National de la the design and conduct of the study; collection, Vigevano, MD, U.O. Neurologia Dipartimento di Santé et de la Recherche Médicale Unite 1141, Paris, management, analysis, and interpretation of the Neuroscienze Ospedale Pediatrico Bambino Gesù, France (Auvin). data; preparation, review, or approval of the IRCCS, Rome, Italy; Antonio Gil-Nagel, MD, Hospital manuscript; and decision to submit the manuscript Ruber Internacional Planta Servicio de Neurologia, Author Contributions: Dr Nabbout had full access for publication. to all of the data in the study and takes Madrid, Spain; Victoria San Antonio, MD, Hospital responsibility for the integrity of the data and the Group Information: The Fenfluramine Assessment Sant Joan de Déu, Barcelona, Spain; Rocio accuracy of the data analysis. in Rare Epilepsy (FAiRE), DS Investigators are Sanchez-Carpintero, MD, Clinica Universitaria de Concept and design: Nabbout, Mistry, Gil-Nagel, Deepak Gill, MBBS, The Children’s Hospital Navarra Fase 4. Segunda planta, Consulta de Chiron, Farfel, Galer, Lock, Auvin. Westmead, Westmead, New South Wales, Australia; Pediatria, Pamplona, Spain; J. Helen Cross, MBChB, Acquisition, analysis, or interpretation of data: Kate Riney, MBBCh, Children’s Health Queensland Great Ormond Street Hospital for Children NHS Nabbout, Mistry, Zuberi, Villeneuve, Gil-Nagel, Hospital and Health Service at Lady Cilento Foundation Trust, London, United Kingdom; Sanchez-Carpintero, Stephani, Laux, Wirrell, Knupp, Children’s, South Brisbane, Queensland, Australia; Archana Desurkar, MD, Sheffield Children’s Farfel, Galer, Morrison, Lock, Agarwal, Auvin. Ingrid Scheffer, MBBS, Melbourne Brain Centre Hospital, Sheffield, United Kingdom; Elaine Drafting of the manuscript: Nabbout, Mistry, Austin Hospital, Melbourne, Victoria, Australia; Hughes, MD, Evelina Hospital, London, United Sanchez-Carpintero, Galer, Lock, Agarwal. Berten Ceulemans, MD, Universitair Ziekenhuis Kingdom; Anand Iyer, MD, Alder Hey Hospital, Critical revision of the manuscript for important Antwerpen, Antwerp, Belgium; Jeffrey Buchhalter, Liverpool, United Kingdom; Sunny Philip, MD, intellectual content: All authors. MD, Alberta Children’s Hospital Childrens Birmingham Children’s Hospital, Birmingham, Statistical analysis: Mistry, Farfel, Galer, Lock. Comprehensive Epilepsy Centre, Calgary, Alberta, United Kingdom; Sameer Zuberi, MD, Institute of Obtained funding: Farfel. Canada; Lionel Carmant, MD, Centre Hospitalier Neurosciences Queen Elizabeth University Administrative, technical, or material support: Universitaire Sainte-Justine, Montreal, Quebec, Hospital, Glasgow, United Kingdom; Gregory Sharp, Mistry, Zuberi, Stephani, Wirrell, Agarwal, Auvin. Canada; Mary Connolly, MBBCh, British Columbia MD, Arkansas Children’s Hospital Research Supervision: Nabbout, Mistry, Gil-Nagel, Children’s Hospital, Vancouver, British Columbia, Institute, Little Rock, Arkansas; Frank Berenson, Sanchez-Carpintero, Farfel, Galer. Canada; Marina Nikanorova, MD, Danish National MD, Panda Neurology, Atlanta, Georgia; Orrin Epilepsy Centre, Dianalund, Denmark; Rima Devinsky, MD, Institute of Neurology and Conflict of Interest Disclosures: Drs Nabbout, Nabbout, MD, Hôpital Universitaire Necker–Enfants Neurosurgery at St Barnabas, Livingston, New Auvin, Zuberi, Villeneuve, Gil-Nagel, Malades, Paris, France; Stephane Auvin, MD, Jersey; Kelly Knupp, MD, Children’s Hospital Sanchez-Carpintero, Stephani, Laux, Wirrell, Knupp, Hôpital Robert Debré, Paris, France; Claude Cances, Colorado, Aurora; Linda Laux, MD, Ann & Robert H. and Chiron report research support from Zogenix MD, Hôpital Des Enfants Pédiatre Médicale, Paris, Lurie Children’s Hospital of Chicago, Chicago, outside the submitted work. Drs Farfel, Galer, France; Frederic Villega, MD, Hôpital Des Enfants– Illinois; Eric Marsh, MD, Children’s Hospital of Morrison, Mistry, and Agarwal are employees of and Groupe Hospitalier Pellegrin, Bordeaux, France; Philadelphia, Philadelphia, Pennsylvania; Mark owners of stock from Zogenix. Dr Lock reported Audrey Riquet, MD, Hôpital Jeanne De Flandre, Nespeca, MD, Rady Children’s Hospital San Diego, receiving personal fees as a consultant to Zogenix Lille, France; Dorethee Ville, MD, Hôpital San Diego, California; Ian Miller, MD, Miami both during the conduct of this study and outside Femme-Mére-Enfant, Bron, France; Nathalie Children’s Hospital Brain Institute, Miami, Florida; of the submitted work. Dr Sanchez-Carpintero also Villeneuve, MD, Hôpital de la Timone, Marseille, Robert Nahouraii, MD, OnSite Clinical Solutions LLC, reported personal fees and other support from France; Patrick Berquin, MD, Chu Amiens Picardie Charlotte, North Carolina; Juliann Paolicchi, MD, GWPharma outside the submitted work and Service de Neurologie Pediatrique, Amiens, France; Northeast Regional Epilepsy Group, Hackensack, unremunerated membership in the Scientific Ulrich Brandl, MD, Universitaetsklinikum Jena Klinik New Jersey; Steven Phillips, MD, MultiCare Institute committee for Fundación Síndrome de Dravet. fuer Kinder- und Jugendmedizin Neuropaediatrie, for Research & Innovation, Tacoma, Washington; Dr Stephani also reported being part of the advisory Jena, Germany; Julia Jacobs-LeVan, MD, Michael Scott Perry, MD, Cook Children’s Medical board of Zogenix and a speaker at a Zogenix Universitaetsklinikum Freiburg Zentrum fuer Center, Fort Worth, Texas; Annapurna Poduri, MD, industrial symposium during an international Kinder- und Jegendmedizin Klinik fuer Boston Children's Hospital, Boston, Massachusetts; congress. Dr Knupp also reported personal fees Neuropaediatrie und Muskelerkrankungen, Ben Renfroe, MD, Northwest Florida Clinical from GWPharma, Stoke Therapeutics, and Biomarin Freiburg, Germany; Thomas Mayer, MD, Research Group, LLC, Gulf Breeze; Russell Saneto, and grants from West Therapeutics outside the Kleinwachau Saechsisches Epilepsiezentrum DO, Seattle Children’s Hospital, Seattle, submitted work. Dr Chiron also reported personal Radeberg gemeinnuetzige GmbH, Radeberg Washington; Asim Shahid, MD, University Hospitals fees from Advicenne, Biocodex, Orphelia, UCB, and (Sachsen), Germany; Axel Panzer, MD, DRK Kliniken Cleveland Medical Center, Cleveland, Ohio; Douglas Zogenix outside the submitted work. Dr Farfel Berlin–Westend, Epilepsiezentrum/ Smith, MD, Minnesota Epilepsy Group, PA, St Paul; reported the following patents pending: Neuropaediatrie, Berlin, Germany; Tilman Polster, Marcio Sotero de Menezes, MD, Swedish Epilepsy US20180092864, US20190125697, MD, Krankenhaus Mara Epilepsie-Zentrum Bethel, Center, Seattle, Washington; Joseph Sullivan, MD, US20190091173, US20190091174, and 2 additional Bielefeld, Germany; Milka Pringsheim, MD, Schoen University of California San Francisco, San unpublished patent applications. Dr Galer also Klinik Vogtareuth Neuropaediatrie und Francisco; Matthew Sweney, MD, University of reported support from Zogenix outside the Neurologische Rehabilitation, Epilepsiezentrum Utah, Salt Lake City; Dinesh Talwar, MD, Center for submitted work and patent to Zogenix. Dr Morrison fuer Kinder und Jugendlische, Tagesklinik fuer Neurosciences–Tucson, Tucson, Arizona; Elizabeth also reported personal fees from Zogenix outside Neuropaediatrie, Vogtareuth, Germany; Ulrich Thiele, MD, Massachusetts General Hospital, the submitted work; in addition, Dr Morrison had Stephani, MD, Universitaetsklinikum Boston; James Wheless, MD, Le Bonheur Children's the following patents pending: US20190091179, Schleswig-Holstein Campus Kiel, Klinik fuer Hospital, Memphis, Tennessee; Angus Wilfong, MD, US20190091175, US20190091176, Neuropaediatrie, Kiel, Germany; Markus Wolff, MD, Phoenix Children's Hospital, Phoenix, Arizona; US20190091177 and another unpublished patent.

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Elaine Wirrell, MD, Mayo Clinic, Rochester, 11. Chiron C, Helias M, Kaminska A, et al. Do 23. Webb RH, Gentles TL, Stirling JW, Lee M, Minnesota; Mary Zupanc, MD, Children's Hospital of children with Dravet syndrome continue to benefit O’Donnell C, Wilson NJ. Valvular regurgitation using Orange County, Orange, California. from stiripentol for long through adulthood? portable echocardiography in a healthy student Meeting Presentation: This study was presented Epilepsia. 2018;59(9):1705-1717. doi:10.1111/epi.14536 population: implications for rheumatic heart as a poster at the American Epilepsy Society Annual 12. Lagae L, Sullivan J, Helen Cross J, et al. ZX008 disease screening. J Am Soc Echocardiogr. 2015;28 Meeting, November 30-December 4, 2018; New (fenfluramine HCl oral solution) in Dravet (8):981-988. doi:10.1016/j.echo.2015.03.012 Orleans, Louisiana. syndrome: results of a phase 3, randomized, 24. Bachorik L. FDA announces withdrawal Additional Contributions: Syneos Health assisted double-blind, placebo-controlled trial. Lancet.in fenfluramine and dexfenfluramine (Fen-Phen). with statistical analysis. Medical writing and press. https://wayback.archive-it.org/7993/ editorial assistance were provided by Danielle 13. Rubino C, Boyd B, Zhang L, Ismail M, Trang M, 20170723090512/https://www.fda.gov/Drugs/ Ippolito, PhD, CMPP, MWC, and Courtney Breuel, Farfel GM. ZX008 (fenfluramine oral solution) as DrugSafety/ ELS, PharmaWrite LLC and funded by Zogenix. adjunctive therapy for Dravet syndrome seizures: PostmarketDrugSafetyInformationforPatien tsandProviders/ucm179871.htm. Published 1997. Data Sharing Statement: See Supplement 4. a pharmacometric approach to quantify potential drug-drug interactions to support phase 3 dose Accessed May 29, 2018. REFERENCES selection. Annual Meeting of the America Epilepsy 25. Abenhaim L, Moride Y, Brenot F, et al; Society; December 1-5, 2017; Washington, DC. International Primary Pulmonary Hypertension 1. Wirrell EC, Laux L, Donner E, et al. Optimizing the 14. U.S. Department of Health and Human Services Study Group. Appetite-suppressant drugs and the diagnosis and management of Dravet syndrome: risk of primary pulmonary hypertension. N Engl J recommendations from a North American Food and Drug Administration. Center for Drug Evaluation and Research; Center for Biologics Med. 1996;335(9):609-616. doi:10.1056/ consensus panel. Pediatr Neurol. 2017;68:18-34.e3. NEJM199608293350901 doi:10.1016/j.pediatrneurol.2017.01.025 Evaluation and Research. E6(R2) Good clinical practice: integrated addendum to ICH E6(R1) 26. Dahl CF, Allen MR, Urie PM, Hopkins PN. 2. Wu YW, Sullivan J, McDaniel SS, et al. Incidence guidance for industry. https://www.fda.gov/media/ Valvular regurgitation and surgery associated with of Dravet syndrome in a US population. Pediatrics. 93884/download. Published March 2018. Accessed fenfluramine use: an analysis of 5743 individuals. 2015;136(5):e1310-e1315. doi:10.1542/peds.2015-1807 October 28, 2019. BMC Med. 2008;6:34. doi:10.1186/1741-7015-6-34 3. Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar 15. Boyd B, Smith S, Gammaitoni A, Galer BS, 27. Hopkins PN, Polukoff GI. Risk of valvular heart O. Severe myoclonic epilepsy in infancy: Dravet Farfel GM. A phase I, randomized, open-label, disease associated with use of fenfluramine. BMC syndrome. Adv Neurol. 2005;95:71-102. single-dose, 3-period crossover study to evaluate Cardiovasc Disord. 2003;3:5. doi:10.1186/1471-2261- 4. Depienne C, Trouillard O, Saint-Martin C, et al. the drug-drug interaction between ZX008 3-5 Spectrum of SCN1A gene mutations associated with (fenfluramine HCl oral solution) and a regimen of 28. Jick H, Vasilakis C, Weinrauch LA, Meier CR, Dravet syndrome: analysis of 333 patients. J Med stiripentol, clobazam, and valproate in healthy Jick SS, Derby LE. A population-based study of Genet. 2009;46(3):183-191. doi:10.1136/jmg.2008. subjects. Int J Clin Pharmacol Ther. 2019;57(1):11-19. appetite-suppressant drugs and the risk of 062323 doi:10.5414/CP203276 cardiac-valve regurgitation. N Engl J Med. 1998;339 5. Skluzacek JV, Watts KP, Parsy O, Wical B, 16. Sabaz M, Lawson JA, Cairns DR, et al. Validation (11):719-724. doi:10.1056/NEJM199809103391102 Camfield P. Dravet syndrome and parent of the quality of life in childhood epilepsy 29. Rich S, Rubin L, Walker AM, Schneeweiss S, associations: the IDEA League experience with questionnaire in American epilepsy patients. Abenhaim L. Anorexigens and pulmonary comorbid conditions, mortality, management, Epilepsy Behav. 2003;4(6):680-691. doi:10.1016/j. hypertension in the United States: results from the adaptation, and grief. Epilepsia. 2011;52(suppl 2): yebeh.2003.08.012 surveillance of North American pulmonary 95-101. doi:10.1111/j.1528-1167.2011.03012.x 17. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: hypertension. Chest. 2000;117(3):870-874. doi:10. 6. Cooper MS, Mcintosh A, Crompton DE, et al. reliability and validity of the Pediatric Quality of Life 1378/chest.117.3.870 Mortality in Dravet syndrome. Epilepsy Res. 2016; Inventory version 4.0 generic core scales in healthy 30. Schoonjans A, Paelinck BP, Marchau F, et al. 128:43-47. doi:10.1016/j.eplepsyres.2016.10.006 and patient populations. Med Care. 2001;39(8): Low-dose fenfluramine significantly reduces 7. Harden C, Tomson T, Gloss D, et al. Practice 800-812. doi:10.1097/00005650-200108000- seizure frequency in Dravet syndrome: guideline summary: sudden unexpected death in 00006 a prospective study of a new cohort of patients. Eur epilepsy incidence rates and risk factors: report of 18. Ziobro J, Eschbach K, Sullivan JE, Knupp KG. J Neurol. 2017;24(2):309-314. doi:10.1111/ene.13195 the guideline development, dissemination, and Current treatment strategies and future treatment 31. Lai WW, Pringsheim M, Farfel G, et al. implementation subcommittee of the American options for Dravet syndrome. Curr Treat Options Long-term cardiovascular safety of Fintepla® Academy of Neurology and the American Epilepsy Neurol. 2018;20(12):52. doi:10.1007/s11940-018- (fenfluramine HCl oral solution) in the treatment of Society. Epilepsy Curr. 2017;17(3):180-187. doi:10. 0537-y Dravet syndrome: interim analysis of an open-label 5698/1535-7511.17.3.180 19. Chiron C. Stiripentol for the treatment of Dravet safety extension study [poster]. American Epilepsy 8. Aras LM, Isla J, Mingorance-Le Meur A. syndrome. Orphan Drugs Res Rev. 2014;4:29-38. Society (AES) Annual Meeting; November The European patient with Dravet syndrome: doi:10.2147/ODRR.S47619 30–December 4, 2018; New Orleans, LA. results from a parent-reported survey on 20. Chiron C, Marchand MC, Tran A, et al. 32. Schoonjans AS, Marchau F, Paelinck BP, et al. antiepileptic drug use in the European population Stiripentol in severe myoclonic epilepsy in infancy: Cardiovascular safety of low-dose fenfluramine in with Dravet syndrome. Epilepsy Behav. 2015;44: a randomised placebo-controlled Dravet syndrome: a review of its benefit-risk profile 104-109. doi:10.1016/j.yebeh.2014.12.028 syndrome-dedicated trial. STICLO study group. in a new patient population. Curr Med Res Opin. 9. De Liso P, Chemaly N, Laschet J, et al. Patients Lancet. 2000;356(9242):1638-1642. doi:10.1016/ 2017;33(10):1773-1781. doi:10.1080/03007995.2017. with Dravet syndrome in the era of stiripentol: S0140-6736(00)03157-3 1355781 a French cohort cross-sectional study. Epilepsy Res. 21. European Medicines Agency. Diacomit: 33. Ceulemans B, Boel M, Leyssens K, et al. 2016;125:42-46. doi:10.1016/j.eplepsyres.2016.05.012 EPAR—scientific discussion. https://www.ema. Successful use of fenfluramine as an add-on 10. Harden C, Tomson T, Gloss D, et al. Practice europa.eu/en/documents/scientific-discussion/ treatment for Dravet syndrome. Epilepsia. 2012;53 guideline summary: Sudden unexpected death in diacomit-epar-scientific-discussion_en.pdf. (7):1131-1139. doi:10.1111/j.1528-1167.2012.03495.x epilepsy incidence rates and risk factors: report of Published January 29, 2009. Accessed February 34. Ceulemans B, Schoonjans AS, Marchau F, the Guideline Development, Dissemination, and 28, 2019. Paelinck BP, Lagae L. Five-year extended follow-up Implementation Subcommittee of the American 22. Devinsky O, Cross JH, Laux L, et al; Cannabidiol status of 10 patients with Dravet syndrome treated Academy of Neurology and the American Epilepsy in Dravet Syndrome Study Group. Trial of with fenfluramine. Epilepsia. 2016;57(7):e129-e134. Society. Neurology. 2017;88(17):1674-1680. doi:10. cannabidiol for drug-resistant seizures in the Dravet doi:10.1111/epi.13407 1212/WNL.0000000000003685 syndrome. N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618

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